The overall goal of the proposed research is to develop pragmatic strategies to prevent hyperoxic lung injury in preterm infants with respiratory distress syndrome requiring ventilatory support. The surfactant system and the protective antioxidant enzyme system of the lung share a chronologically similar late gestational pattern of maturation, preparing the lung for the safe initiation of breathing room air. Glucocorticoid, thyroid hormone, thyrotropin-releasing hormone, epidermal growth factor, and retinoic acid have been found to induce growth and development of the fetal lung and its surfactant system. The combination of maternal glucocorticoid and postnatal surfactant replacement therapy effectively reduces the severity of respiratory distress syndrome in preterm infants. However, continuing lung immaturity and breathing irregularities may expose the preterm infant to prolonged periods of mechanical ventilation, resulting in chronic lung injury when oxidant injury overwhelms the limited antioxidant capacity of the preterm lung. Accelerated maturation of the lung antioxidant enzyme system may reduce the occurrence and severity of chronic lung injury in the preterm infant. Corticosteroids stimulate and thyroid hormone and thyrotropin-releasing hormone depress fetal lung antioxidant enzyme activity, but the effects of epidermal growth factor and retinoic acid are largely unknown. We propose to study whether epidermal growth factor and retinoic acid advance the maturation of the fetal lung antioxidant system and whether antenatal hormonal priming of the antioxidant enzyme system with postnatal supplementation of antioxidant enzymes prevent the emergence of hyperoxic lung injury in the newborn rat.